Pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) is one of the most lethal malignant diseases with worse prognosis and, it is the 4th most common cause of cancer-related deaths in both men and women in the United States. Because pancreatic cancer is a major public health concern, the development of new therapeutic strategies for the treatment of this devastating disease is highly challenging and significant. The PI3K-Akt-mTOR and MAPK pathways are highly deregulated in pancreatic cancer. Recent studies have also implicated the most downstream signaling component of these pathways, eIF4F (specifically, eIF4E-Mnk1/2 axis) that control gene expression at the translational level towards PDAC development and to de novo and acquired drug resistant. The significance of this finding is underscored by the tremendous therapeutic potential for targeting this downstream oncogenic nexus in human PDAC and indeed other cancers impacted by these dysfunctions. In the course of studies to develop potent androgen receptor degrading agents (ARDAs) to modulate AR signaling in prostate cancer models (1), we discovered that these novel ARDAs also effectively target oncogenic eukaryotic protein translation, via modulation of Mnk- eIF4E axis. We note that these targets have been implicated in the development, progression, metastasis and drug resistance of PDAC (2-5). In addition, by targeting Mnk-eIF4E which is downstream of KRAS oncogene, we could for the first time effectively suppress the action of KRAS, a mutated oncogene present ~90% of PDAC tumors (6). We also discovered that these ARDAs are not only effective against prostate cancer cells and tumors but they are also effective anti-pancreatic cancer agents. Our preliminary results clearly demonstrate a potential use of ARDAs (VN/124-1 or galeterone and related analogs) for effective treatment of PDAC. The objective of this proposal is to test this hypothesis by blocking both Mnk-eIF4E activity in preclinical cell culture and animal models of pancreatic cancer, and will do this by using our novel ARDAs, VN/124-1 (Galeterone or TOK-001; that is poised to enter phase 3 clinical trials in castration-resistant prostate cancer patients) and its more efficacious analogs VNPP414 and VNPP433-3, which should facilitate rapid translation if these preclinical studies show promising activity. Three specific aims will be pursued: 1) Design and develop practical synthesis of highly promising novel ARDAs, VNPP414 and VNPP433-3. 2) Determine the anti-cancer activities, mechanisms of action of lead ARDAs alone and in combination with gemcitabine (the elective drug for PDAC therapy). 3) To assess the in vivo anti-tumor and anti-metastatic efficacies of lead ADRAs in a xenograft, orthotopic and patient-derived xenograft of PDAC. This project is expected to generate new information to lay a solid foundation for future extensive mechanistic studies as well as advanced preclinical development and assessment of the oncogenic potential of targeting Mnk-eIF4E signaling as a means to novel and improved therapeutic for pancreatic cancer through other NIH funding mechanisms and possibly partnering with big/small pharmaceutical companies. We believe that the results from the proposed study will provide strong preclinical proof-of-concept for the use of multi-target ARDAs as a novel therapeutic strategy in the treatment of pancreatic cancer in humans.